Behavioural pain measurements. Von Frey hair mechanosensitivity. Von Frey hair mechanosensitivity was used as a measure of secondary allodynia . Von Frey hair mechanosensitivity. Von Frey hair mechanosensitivity was used as a measure of secondary allodynia. Alert, unanaesthetised animals were . Von Frey (vF) filaments are a series of nylon monofilaments which are graded in .. up and down method of Dixon () (see section: ). included an animal's stood on a floor contains a mechanosensitive transducer measuring.
hair 2.4.1. Von mechanosensitivity Frey
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Patients were screened daily, based on obstetric chart. Consent was obtained 1—7 days before surgery. Scar hyperalgesia and pain in repeat Caesarean delivery C. No pre-medication was given, except for aspiration.
Caesarean delivery was performed using a low trans-. As per standard clinical practice at each institution,. Additional oral oxycodone 10 mg was available for. HSJM, women received oral diclofenac 50 mg every.
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Appendix 2, questions 11c, 12b Eisenach et al. Women were asked to report their pain intensity on. Scar hyperalgesia and pain in repeat Caesarean delivery. Intravenous morphine equivalents ivMEQs were calcu-. Pre- and post-operative hyperalgesia and mTS mea-. T wo investigators at each site. The sample size was based on a pilot analysis after The decision to choose V AS-S48 as the. The pilot analysis after inclusion of 20 cases at. Parametric data are presented as mean and standard.
In order to control for multiple testing, a hierarchical. Data were split into two study. Secondary outcomes including all post-operative. If the null hypothesis was rejected, Pearson correla-. To evaluate the validity of the model using preopera-. Patient demographics, SHA, primary and secondary. The screening process to identify eligible participants. Caesarean delivery, which was on average 55 There were no dif fer-. Time from previous Caesarean delivery was similar in.
There was no correlation between time. In the group of women with no preoperative. Moderate to severe pain upon mobilization at 48 h.
Table 1 Demographic data. Weight kg 84 19 98 29 80 12 0. Height cm 16 7 7 0. Time interval from previous Caesarean delivery months 55 33 44 25 64 37 0. Data are presented as mean and standard deviation. Table 2 Preoperative tests and post-operative pain outcomes according. Preoperative mT S 0— 0 [0; 8] 9 [0. WHA at 48 h index 0 [0; 0. Data are presented as mean and standard deviation or median and quar-. Wilcoxon rank sum test for non-parametric data. The incidence and extent of post-.
Pain upon mobilization was evaluated by asking. Preoperative SHA index was corre-. As mTS scores were different between. There was no difference. However, overall higher rescue. Figure 2 Correlation between preoperativ e scar hyperalgesia SHA and.
Solid line is the corre-. Figure 1 Post-operative pain w as tested on a point visual analogue. With the exception of VAS-R24, pain scores w ere. Table 3 Preoperative scar hyperalgesia as pain prediction test. SHA, preoperative scar hyperalgesia. We evaluated both scar preoperatively hyperalge-. The incidence and extent of sec-. Finally, Ilkjaer et al.
Such differences in the incidence of post-incisional. Presented as an extent, the hyperal-. The problem with using an area is that.
To the best of our knowledge, no previous study has. Besides identifying that SHA was present in a large. As in our study , women with preopera-.
We found a correlation between SHA index and. It is agreed that central. Our model is able to. Overall post-operative analgesic use did not differ. There was a strong correlation between preopera-. In the context of our study , time. Temporal summation, used as marker for wind-up. Establishing the relation between. In contrast, Brandsborg et al. A variety of quantitative sensory tests to predict. We selected hyperalgesia and mTS as.
We acknowledge that the main limitation of this. Different analgesic regimens as well. Caesarean delivery have SHA.
We would like to thank the committee of the Society of. Further, we would like to thank our research assistants. A qualitative systematic review. Mechanosensitivity before and after. A prospective study on the prediction of acute. Br J Anaesth , — Pronociceptive effects of remifentanil in a mouse.
Effect of a second surgery. Reliability of temporal summation and diffuse noxious inhibi-. Pain Res Manag 14, — Secondary hyperalgesia is not. Anaesthesiol Scand 41, — Br J Anaesth 74, —. EFNS guidelines on neuropathic pain assessment:. Eur J Neurol 17, — Anesth Analg , —; table of contents. Severity of acute pain after childbirth,.
Palliat Med 2, — Can we predict persistent postoperative pain. Post-Cesarean section pain prediction by preop-. The effect of post-. Eur J Pain 16, — Prog Neurobiol 61, — Effect of preoperative oral dextromethorphan on. An experimental paradigm for the Predic-. J Vis Exp 35 , pii: J Pain 10, — Chronic pain after vaginal and Cesar-. A reality questioning our daily practice of obstet-.
Int J Obstet Anesth 19, 1—2. An evaluation of the postoperative anti-. Postoperative analgesic effects of continuous wound. Chronic secondary hypersensitivity of. Dextromethorphan and pain after total abdominal. Br J Anaesth 81, — Effects of affective picture modulation. Acta Anaesthesiol Belg 61, 55— Does magnesium sulfate reduce.
Am J Obstet Gynecol , —; discussion —. Multifactorial preoperative predictors for post-Cesarean. Hyperalgesia and temporal summation of pain after. Fentanyl enhancement of carrageenan-.
N-methyl-D-aspartate receptor antagonist ketamine. A comprehensive protocol for clinical trials. Eur J Pain 10,. Are they all equally dan-. J Pain Symptom Manage 38, — Pain catastrophizing, response to.
Mapping of punctuate hyperalgesia around a surgical. Preemptive effect of fentanyl and ketamine. Central mechanisms in pain. Med Clin North Am 83, — Prevalence and predictors of chronic pain. Curr Opin Anaesthesiol 23, — Caesarean delivery rates and pregnancy outcomes:. The WHO global survey on maternal and perinatal. Prediction of postoperative pain: A systematic review of pre-. Postoperative sensitization and pain after Cesarean.
Anesth Analg 97, —. Chronic pain and surgery: J Pain Palliat Care Phar-. Its clinical importance and relevance. Patients with chronic pain after abdominal surgery. J Pain Palliat Care. Contemporary Cesarean delivery practice in the.
Am J Obstet Gynecol , e— e If no change in sensation appeared, stimulation. The SHA index was calculated as sum of distances to. Phone number for follow-up calls: Preferred method and time of day to be contacted: What is the country of origin of your four grandparents? What is your general state of health? Have you had chronic pain that started before this pregnancy? Were you taking daily pain medications before this pregnancy?
If YES, please list the medicines and amounts:. Do any members of your family parents, brother or sister, uncle, aunt or close cousins have a problem with. Condition name if known: Do you usually have much pain with your menstrual bleeding? If YES, have you seen a physician for evaluation of the problem?
Were you seeing a doctor regularly for any medical problems in the year before your pregnancy? If YES, the reason I was seeing the doctor was check all that apply. In the year before your pregnancy , did you smoke cigarettes more than 1 pack per week.
Have you had any problems after any previous operations? If you had a problem noted above, type of operation. Did you have any problems after the birth of any previous baby?
The molecular basis for the positive actions of exercise remains poorly understood. The results indicated that moderate exercise training reduced widespread hyperalgesia, whereas the effect of mild exercise training was less robust. Likewise, moderately-intense exercise training upregulated NT-3 synthesis in the skeletal muscle; mild exercise training had no effect of NT-3 levels.
In addition, the protein levels were significant only in the gastrocnemius and not in the soleus muscle, suggesting that exercise can preferentially target NT-3 synthesis in specific muscles. In summary, this body of work indicates a novel finding of chronic muscle pain and adds new information to our understanding of deep tissue nociception as well as its spinal distribution.
This study is the first to demonstrate the beneficial effect of aerobic exercise training on chronic muscle pain in the acid-pain model. These results strengthen the role of NT-3 as an anti-nociceptive neurotrophin in treating muscle pain and provide further support for exercise training as a therapeutic intervention for the growing field of pain medicine.
Aug J Pain. Most of our knowledge about chronic musculoskeletal pain is based on cutaneous pain models. To test the hypothesis that animals develop chronic muscular hyperalgesia following intramuscular acidic saline injections, primary hyperalgesia within the gastrocnemius muscle was analyzed compared to secondary cutaneous hyperalgesia in the hind paw that develops following intramuscular acid saline injection.
Two acidic saline pH 4 injections were administrated into the gastrocnemius of female CF-1 mice. The results indicate that mice developed a robust hypersensitivity bilaterally in primary gastrocnemius muscle secondary cutaneous hind paw sites that lasted up to 2 weeks. In addition, primary hyperalgesia correlated well with levels of Fos expression.
Fos expression patterns in the spinal cord were different for primary secondary site stimulation. In contrast, gastrocnemius compression stimulated widespread Fos expression in all regions of the ipsilateral dorsal horn within L2-L6 spinal segments.
These findings indicate that acidic saline injection induces primary hyperalgesia in muscle that the patterns of Fos expression in response to primary vs secondary stimulation are strikingly different. This study assesses primary site muscular pain, which is the main complaint of people with musculoskeletal conditions, and identifies spinal patterns activated by noxious mechanical stimuli to the gastrocnemius.
This study demonstrates approaches to test nociception arising from muscle aids in our understanding of spinal processing of primary secondary site hyperalgesia. Acid-induced experimental muscle pain and hyperalgesia with single and repeated infusion in human forearm. Acid has long been thought to play an important role in the pain process. Animal study showed that repeated acid stimulation induced central sensitization.
The purpose of the study is to investigate muscle pain and hyperalgesia evoked by intramuscular infusion of saline at different pH levels, and to compare the effect of a single versus repeated acid infusions. Twenty healthy subjects received infusions of buffered saline pH 5.
Twelve of the subjects received repeated infusions. The subjects rated the pain intensity on visual analogue scale VAS. Thermal pain sensitivity, and pressure pain threshold PPT were assessed in both arm before, during, immediately after, one hour after, and one day after the infusion.
A McGill Pain Questionnaire and pain mapping were completed after each infusion. The pH 5 solution caused significantly higher pain and larger areas than pH 6.
The local PPTs were significantly decreased hyperalgesia during and immediately after infusion of all three solutions. No significant differences were detected between the first and second infusion. The intensity of acid-induced muscle pain is pH-dependent. All three solutions induced pressure hyperalgesia at the infusion site. Repeated infusions did not induce increased pain or prolonged hyperalgesia as compared with a single injection. Human intramuscular acidic saline infusion could not produce chronic pain model.
The acid-induced pain model may reflect the early stage responses to tissue injury of clinical conditions. Repeated intramuscular acidic saline injection model of prolonged hyperalgesia in rodents could not be translated into a human for modelling chronic musculoskeletal pain.
Inflammation-induced increase in hyperpolarization-activated, cyclic nucleotide-gated channel protein in trigeminal ganglion neurons and the effect of buprenorphine. Hyperpolarization-activated cyclic nucleotide-gated HCN channels are active at resting membrane potential and thus contribute to neuronal excitability. Their increased activity has recently been demonstrated in models of nerve injury-induced pain.
The major aim of the current study was to investigate altered HCN channel protein expression in trigeminal sensory neurons following inflammation of the dura. Western immunoblots of lysates from rat trigeminal ganglia also showed bands with appropriate molecular weights for HCN1 and HCN2. The band densities were normalized against alpha-actin.
When the opioid receptor partial agonist, buprenorphine, was given systemically, immediately after CFA, the inflammation-induced increase in HCN protein expression in both Western blot and immunohistochemical experiments was not observed. These results suggest that HCN1 and HCN2 are involved in inflammation-induced sensory neuron hyperexcitability, and indicate that an opioid receptor agonist can reverse the protein upregulation. Activation of rat masticatory muscle afferent fibres by acidic pH.
Previous research findings have suggested an important role for acid sensing ion channels ASICs in muscle pain mechanisms. This study was conducted to determine if masticatory muscle afferent fibres express ASICs, if there are sex differences in this expression, and to compare the effects of low pH and hypertonic saline on afferent fibres that innervate the masticatory muscle in vivo.
Immunohistochemistry methods were applied to examine the expression of ASICs in trigeminal ganglion neurons, while in vivo electrophysiology techniques were employed to examine changes in masticatory muscle afferent fibre excitability.
No sex-related differences in expression were identified. Injection of pH 5. Since ASIC3 channels are not activated until the pH is around 6, these results indicate that activation of both channels contributes to excitation of masticatory muscle afferent fibres. The results further show that many masticatory muscle afferent fibres, which respond to low pH, are low threshold mechanoreceptors. These findings may explain why injection of low pH solutions into the masticatory muscles of healthy humans is not associated with significant muscle pain.
Masticatory muscle pain may occur following immediate occlusal alteration by dental treatment. The underlying mechanisms are poorly understood. We have developed a rat model of experimental occlusal interference EOI that consistently induces mechanical hyperalgesia in jaw muscles. Rat model of EOI-induced masseter hyperalgesia was established. These changes peaked at day 7 and then returned to original status within 10 days after EOI.
Experimental tissue acidosis leads to increased pain in complex regional pain syndrome CRPS. The aim of this study was to investigate the role of local acidosis in the generation of pain in complex regional pain syndrome CRPS. We investigated ten patients with CRPS of the upper extremity with a mean duration of the disease of 43 weeks range weeks and ten control subjects for sensitivity to infusion of fluids with low pH pH 6.
Another group of five CRPS patients and three healthy controls was investigated using the same protocol but neutral infusion fluid pH 7. A motorized syringe pump was installed for a constant infusion of synthetic interstitial fluid SIF, either acidified pH 6. The magnitude of pain was rated on an electronic visual analogue scale. Patients were requested to give their ratings every 10 s during the whole stimulation period.
The ratings were normalized as fractions of individual grand mean values. Low pH fluid into the skin was significantly more painful between 4 and 6 min ipsi 1. The quality of the deep pain during infusion into the muscle was described by the patients as very similar to the CRPS-related pain. In controls we found no side differences of pain intensity during low pH stimulation. Our results suggest that hyperalgesia to protons is present in patients with CRPS.
Further, we could demonstrate that pain is not only restricted to the skin but is also generated in deep somatic tissue of the affected limb. Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia. Jan Muscle Nerve. This study characterizes an animal model of persistent mechanical hyperalgesia induced by repeated intramuscular injections of low pH saline.
Saline at pH 4, 5, 6, or 7. To quantify hyperalgesia, paw withdrawal latency to radiant heat heat hyperalgesia and withdrawal threshold to mechanical stimuli mechanical hyperalgesia were measured.
Two unilateral injections of low pH saline, 5 days apart, caused a pH-dependent bilateral mechanical, but not heat, hyperalgesia that lasted 30 days. Injections given 2 and 5 days apart produced a significantly greater mechanical hyperalgesia than injections given 10 days apart. Lidocaine injection into the gastrocnemius muscle or unilateral dorsal rhizotomy, 24 h after the second injection pH 4 , had no effect on the contralateral mechanical hyperalgesia.
Minimal histopathology was observed in the injected muscle, and changes were similar between groups injected with pH 4 and pH 7. Thus, this new model of widespread, chronic muscle-induced pain is unrelated to tissue damage and is not maintained by continued primary afferent input from the site of injury. Activation of the cAMP pathway is an important mediator of chronic muscle pain.
Bilateral mechanical hyperalgesia of the paw was induced by administering two injections of acidic saline, 5 days apart, into the gastrocnemius muscle of male Sprague-Dawley rats.
The proportion of spinothalamic neurons that expressed p-NR1 or p-CREB did not change in the dorsal horn 24h after the second intramuscular acid injection compared with animals that received pH 7. This lack of change in spinothalamic neurons in the dorsal horn may be due to increases in individual spinothalamic neurons or increases in non-spinothalamic neurons. There was an increase in the proportion of spinothalamic neurons expressing p-NR1 in lamina X. These findings suggest that there are region-specific changes in spinothalamic neurons that express p-NR1 and lamina X may play an important role in the modulation of chronic muscle pain.
Protons selectively induce lasting excitation and sensitization of nociceptors in rat skin. In ischemic and in inflamed tissues, pH levels down to 5. To evaluate the role of acid pH in nociception, we have studied identified primary afferents in a rat skin-saphenous nerve preparation in vitro where the receptive fields can be superfused at the highly permeable corium side with controlled solutions. Mechanical thresholds were repeatedly tested in a "blind" fashion by von Frey hair stimulation.
In 24 of 96 nociceptor type C- and A delta-fibers, irregular low-frequency discharge with poor response characteristics was induced. Threshold levels were found to range from pH 6. All such fibers responded to CO2 as well as to phosphate-buffered solution at the same pH 6. The CO2 responses, however, displayed significantly shorter latencies and more pronounced dynamic phases.
The carboanhydrase blocker acetazolamide markedly delayed and reduced the CO2 responses. Prolonged application of acid pH 30 min evoked nonadapting activity irrespective of oxygen supply. Many, but certainly not all, fibers sensitive to protons were also driven by capsaicin 10 -6 M, 10 -5 M and vice versa. Repeated or prolonged treatment with low pH induced a significant and lasting decrease of the mechanical von Frey thresholds in almost all C-fibers tested from 35 to 16 mN, on average , and this occurred whether or not a fiber was excited by protons.
The sensitizing effect was more pronounced the higher the initial von Frey thresholds 0. This sensitization to mechanical stimulation was in contrast to the combined action of other inflammatory mediators, bradykinin, 5-HT, histamine and prostaglandin E2.
In conclusion, we suggest that pH sensitivity of nociceptors may be an important source of pain and hyperalgesia. Consideration concerning the neurological basis of muscle pain. Nociceptors in skeletal muscle can be sensitized by substances that are released from pathologically altered tissue. In the sensitized state, nociceptors can be activated by low-intensity stimulation; this is probably one of the mechanisms producing deep tenderness.
Dorsal horn cells processing input from muscle nociceptors often have multiple receptive fields and additional input from other deep tissues or skin. This may be one of the reasons for the diffuse and ill-localized nature of muscle pain.
The degree of convergence from deep tissues and skin in neurones with muscle input can be increased by noxious stimulation of deep tissues. This mechanism might explain phenomena such as spread and referral of muscle pain. In the development of chronic muscle pain, vicious circles may be involved which operate locally in the damaged tissue or via spinal reflexes that alter the biochemical environment of the nociceptors in skeletal muscle.
Diagnosis, Management, Education, and Research. An HRP Study of the central projections from primary sensory neurons innervating the rat masseter muscle. Retrograde and transganglionic transport of horseradish peroxidase has been used to study the cell bodies of origin and the central projections of neurons innervating the rat masseter muscle. Labeled cell bodies were observed both in the trigeminal ganglion and in the mesencephalic trigeminal nucleus.
Major central projections from mesencephalic trigeminal neurons were traced to the supratrigeminal nucleus and to the brainstem reticular formation. Smaller projections from these neurons could be followed to the borders of the solitary tract and hypoglossal nuclei as well as to lamina V of nucleus caudalis and corresponding areas in the dorsal horn at C1-C2 spinal cord segments. Labeling from trigeminal ganglion neurons was observed close to the trigeminal tract in all subdivisions of the trigeminal sensory nuclear complex and in the dorsal horn lamina I at C1 and C2 levels.
A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia.
Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
Relative effectiveness of C primary afferent fibers of different origins in evoking a prolonged facilitation of the? Changes in the excitability of the hamstring flexor withdrawal reflex produced by conditioning stimuli applied to C-afferent fibers of different origins have been examined in the decerebrate spinal rat. In the absence of conditioning stimuli, the flexor reflex elicited by a standard suprathreshold mechanical stimulus to the toes is stable when tested repeatedly for hours.
Three categories of conditioning stimuli have been used in an attempt to modify the excitability of the flexor reflex; electrical stimulation of a cutaneous sural nerve or a muscle gastrocnemius-soleus nerve at C-fiber strength; the application of mustard oil, a chemical irritant that activates chemosensitive C-afferents, to the skin or injected intramuscularly and intraarticularly; and the indirect activation of high-threshold muscle afferents by fused tetanic contractions of the tibial muscles.
Conditioning stimuli of an intensity sufficient to activate C-afferent fibers result in a heterosynaptic facilitation of the flexor motoneuronal response to the standard test input, which lasts from 3 min to more than 3 hr, depending on the stimulus and the C-afferents activated. Pretreatment of the sciatic nerve with the C-fiber neurotoxin capsaicin abolishes all the postconditioning facilitations, which is an indication that it is likely that it is C-afferents that are primarily responsible for the facilitatory effects of the conditioning stimuli, although some A delta afferents may contribute.
Capsaicin pretreatment does not modify the reflex response to the test stimulus. The most prolonged increase in the excitability of the flexor reflex resulted from intraarticular injections of 5 microliter mustard oil. Using the subsequent injection of lignocaine intraarticulary, it was found that the prolonged facilitation of the reflex is triggered by the afferent input generated by the conditioning stimulus and does not require an ongoing input for its maintenance.
These results indicate that there is a spectrum of central changes in the stimulus response relations of the spinal cord resulting from the activation of C-fibers of different origins. The prolonged duration of some of these changes means that the peripheral activation of C-afferents will modify the functional response of the spinal cord to other inputs applied long after the conditioning input, and this may be responsible for some of the sensory and motor alterations found after peripheral tissue injury.
Chronic musculoskeletal pain and depressive symptoms in the National Health and Nutrition Examination. We report here follow-up data on subjects who were examined in two surveys conducted by the United States Center for Health Statistics at an interval of 8 years. From an original sample of subjects, were known to be deceased, leaving a potential sample of cases, of whom were ultimately examined in the NHEFS.
Applying this second definition, the percentage of subjects with chronic pain in the NHANES-1 had risen from 15 to On logistic regression analysis the strongest relationship found at the NHEFS between the variables examined was between chronic pain and depression.
Reliable experimental models are needed to help improve our knowledge of how the central nervous system adapts to function in the presence of muscle pain in man. We developed a microprocessor-based control system for maintaining a constant level of experimental muscle pain. Pain was induced in the relaxed right masseter of healthy young adults by using an infusion pump to inject an algesic 0.
Subjects supplied feedback on their present pain intensity PPI via a 10 cm long electronic visual-analog scale VAS and a 0. Finally, using the pain feedback the adaptive PID controller was successfully used to adjust the infusion rate to maintain PPI in five out of seven healthy adults at a mean SD 4. Mandibular tori, migraine and temporomandibular disorders.
In this study the presence of mandibular tori was related to conditions associated with parafunctional activity. Parafunction in the form of tooth clenching or grinding has been associated with temporomandibular disorders TMD and recently migraine. Patients attending a facial pain clinic in Belfast were assessed for the presence of tori and results compared to age and gender matched controls. The findings were that mandibular tori were present significantly more commonly in both migraineurs and TMD patients.
The results support an association with parafunction in the aetiology of mandibular tori and suggest that tori are a useful marker of past or present parafunction in some patients. Pain due to tissue acidosis: A mechanism for inflammatory and ischemic myalgia? To study the role of protons in ischemic muscle pain we employed the "submaximal effort tourniquet technique' and, in a second attempt, an intramuscular pressure infusion of acid phosphate buffer. The pH measured in the forearm skin covering the muscles at work during the tourniquet test continuously dropped to a mean value of pH 7.
After restoring the blood supply, the intradermal proton concentration decreased more slowly than the muscular pain. The same subjective quality of deep muscular pain was achieved with pressure infusion of acid phosphate buffer pH 5. Changes in flow rate were followed by changes in pain ratings with a certain phase lag. We conclude that muscular pain induced by infusion of acidic phosphate buffer and pain from ischemic contractions are generated through the same mechanisms based on the algogenic action of protons.
Inflammatory mediators potentiate pain induced by experimental tissue acidosis. Electrophysiological evidence from cutaneous nociceptors suggested a synergism between excitatory actions of inflammatory mediators IM and low pH. In human skin it is possible to induce constant ongoing pain with continuous infusion of acid buffer.
This method was used to study the interaction with mediators of inflammation psychophysiologically. A skin area on the palmar forearm of 6 subjects either gender, age years was continuously infiltrated with a phosphate buffered electrolyte solution pH 5.
Pain was assessed on the VAS at sec intervals; the rating was called up by means of an acoustic signal. An additional cannula was placed in the skin before the infusion of acidic buffer started. The other arm was used for negative control, i. IM in neutral solution were injected into normal skin continuously infiltrated with a buffer solution at pH 7. The difference corresponded to a fold increase in algogenic potency with 10 -7 M IM, being smaller with 10 -6 and 10 -5 M concentration.
The interaction between low pH and IM was mutual: Thus, we tend to conclude that it is the inflammatory mediators that potentiate the algogenic effect of low pH rather than vice versa. Tissue acidosis appears as a dominant factor in inflammatory pain. Tissue acidosis in nociception and pain. Feb Progr Brain Res. An acid sensing ion channel ASIC localizes to small primary afferent neurons in rats. The acid sensing ion channel ASIC identified in rat brain and spinal cord is potentially involved in the transmission of acid-induced nociception.
We have developed polyclonal antisera against ASIC, and used them to screen rat brain and spinal cord using immunocytochemistry. ASIC-immunoreactivity -ir is present in but not limited to the superficial dorsal horn, the dorsal root ganglia DRG and the spinal trigeminal nucleus, as well as peripheral nerve fibers. Effects of adjuvant on neuropeptide-like immunoreactivity in the temporomandibular joint and trigeminal ganglia.
To study the role of the nervous system in temporomandibular joint arthritis, substance P-, calcitonin gene-related peptide-, and neuropeptide Y-like immunoreactivity in the trigeminal ganglia and temporomandibular joint of rats was examined. Arthritis was induced in female Lewis rats through bilateral injection of a suspension of heat-killed Mycobacterium butyricum in paraffin oil into the temporomandibular joint.
Control rats received paraffin oil via the same route. Tissues were collected for neuropeptide extraction 28 days after injection and analyzed by radioimmunoassay and reverse-phase high-performance liquid chromatography.
Calcitonin gene-related peptide was significantly increased in the arthritic trigeminal ganglia. Substance P, calcitonin gene-related peptide, and neuropeptide Y in the arthritic temporomandibular joint were significantly increased as compared to controls.
The results of this study show that sensory and sympathetic neuropeptides may possibly be associated with the development of arthritis in the temporomandibular joint of rats. Visualization of chronic neck-shoulder pain: Impaired microcirculation in the upper trapezius muscle in chronic cervico-brachial pain.
Changes in trapezius muscle blood flow and EMG were examined and related to the anamnesis and physical findings. The microcirculation in the upper part of the right and left trapezius muscles was examined simultaneously by using optical laser-Doppler single-fibres after insertion into the muscle directly via the skin.
Continuous recordings were made during stepwise increased static contraction determined electro-myographically. Signal processing was performed on-line by computer. MRT of the cervical spine was performed in 12 patients. None showed nerve root affliction. Ten showed a bulging intervertebral disc and two, a narrowed nerve hole lateral stenosis. The muscle blood flow LDF was significantly lower in the most painful side compared with the opposite side in the group of 41 patients with predominantly unilateral pain 21 women and 20 men.
A lowered blood flow was also found when the 21 females in this group was compared with a normal control group of 20 healthy women. A further lowering of the MPF was observed with induced fatigue. It was concluded that the chronic neck pain in cervico-brachial syndrome can become visualized by the finding of lowered blood flow of the trapezius muscle which seems to be an expression of the chronic neck pain.
Inflammation-induced increase in the density of neuropeptide-immunoreactive nerve ending in rat skeletal muscle. The density of substance P SP -, calcitonin gene-related peptide CGRP - and vasoactive intestinal polypeptide VIP -immunoreactive ir nerve endings was quantitatively evaluated in intact and inflamed gastrocnemius-soleus muscle of the rat.
In persistently inflamed muscle 12 days after a single injection of Freund's adjuvant into the muscle , the density of SP-ir fibres was significantly increased. The data are consistent with the established contribution of NGF on the expression of SP and GAP in afferent neurones under the influence of a persistent inflammation.
Capsaicin, the main pungent ingredient in "hot" chili peppers, elicits buming pain by activating specific vanilloid receptors on sensory nerve endings. The cloned vanilloid receptor VR1 is a cation channel that is also activated by noxious heat. Here, analysis of heat-evoked single channel currents in excised membrane patches suggests that heat gates VR1 directly. VR1 can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit pain.
Immunocytochemical analysis indicates that the receptor is located in a neurochemically heterogeneous population of small diameter primary afferent fibers. A role for VR1 in injury-induced hypersensitivity at the level of the sensory neuron is presented.
Change of trapezius muscle blood flow and electromyography in chronic neck pain due to trapezius myalgia. Chronic neck pain may increase the transmitter activity of neuropeptides in the upper cervical medulla causing impairment of the blood flow in the local muscle because of a lack of vasodilatatory substances excreted axonally.
We have been using a new single-fibre technique for clinical determination of the microcirculation LDF in the trapezius muscles in relation to electromyography EMG. The purpose was to derive more objective medical information upon which to base rehabilitation. Twenty healthy women volunteered to participate as a normal control group. The right and left trapezius muscles of all individuals were examined simultaneously with laser-Doppler flowmetry LDF and surface EMG during a fatiguing series of stepwise-increased contractions, each of 1 min duration with 1 min rest in between.
The most painful side was compared with the opposite side in all patients and, in the female patients, also with the right shoulder of the healthy control women.
The patients showed consistently low local blood flow in the painful side. The difference was statistically significant at low contraction intensities. Muscle tension was somewhat elevated, as evidenced by a slight increase of the rms-EMG that was statistically significant at high contraction intensities.
The lowered local blood flow was not explained by a changed intramuscular pressure which is low in the trapezius during ordinary activities that do not normally impair the local blood flow Larsson, S-E.
A study using percutaneous laser-Doppler flowmetry and surface electromyograpy, Eur. We conclude that an impaired regulation of the microcirculation in the local muscle is of central importance in chronic trapezius myalgia, causing nociceptive pain which can be differentiated objectively from neuralgic neck-shoulder pain by the atraumatic technique described.
A model for predicting chronic TMD: Practical application in clinical settings. Substantial cost is associated with the treatment of chronic temporomandibular disorders, or TMDs, and patients with TMDs often experience significant psychosocial distress.
Early intervention based on identified risk factors has potential financial and functional benefits. Two hundred four patients with acute TMD were evaluated via an assessment battery that included physical, psychological and social measures.
At the six-month follow-up assessment, patients were considered to have chronic TMD if they continued to have TMD pain.
This resulted in of the patients being classified in the chronic group and 60 being classified in the nonchronic group. A comparison of the acute TMD data demonstrated that the group that went on to develop chronic TMD and the group that did not differed significantly in their scores on numerous biopsychosocial indexes.
Although several biopsychosocial measures were found to differentiate these two groups before the onset of chronic TMD, logistic regression analysis demonstrated that a two-variable predictive model consisting of the presence of a muscle disorder and characteristic pain intensity that is, the mean of these three ratings: During the acute phase of TMD, two variables allowed for an accurate prediction rate of 91 percent among patients who went on to develop chronic TMD. This model provides clinicians with the opportunity to identify at-risk patients early and initiate adjunctive or alternative treatments, thus reducing the likelihood of the development of TMD chronicity.
Patients with chronic fatigue syndrome CFS , fibromyalgia FM , and temporomandibular disorder TMD share many clinical illness features such as myalgia, fatigue, sleep disturbances, and impairment in ability to perform activities of daily living as a consequence of these symptoms.
A growing literature suggests that a variety of comorbid illnesses also may commonly coexist in these patients, including irritable bowel syndrome, chronic tension-type headache, and interstitial cystitis.
To describe the frequency of 10 clinical conditions among patients with CFS, FM, and TMD compared with healthy controls with respect to past diagnoses, degree to which they manifested symptoms for each condition as determined by expert-based criteria, and published diagnostic criteria.
Healthy control subjects from a dermatology clinic were enrolled as a comparison group. All subjects completed a item symptom checklist and underwent a brief physical examination performed by the project physicians. In contrast, patients were more likely than controls to meet lifetime symptom and diagnostic criteria for many of the conditions, including CFS, FM, irritable bowel syndrome, multiple chemical sensitivities, and headache.
Individual symptom analysis revealed that patients with CFS, FM, and TMD share common symptoms, including generalized pain sensitivity, sleep and concentration difficulties, bowel complaints, and headache.
However, several symptoms also distinguished the patient groups. Future research that seeks to identify the temporal relationships and other pathophysiologic mechanism s linking CFS, FM, and TMD will likely advance our understanding and treatment of these chronic, recurrent conditions.
Acidosis is associated with inflammation and ischemia and activates cation channels in sensory neurons. Inflammation also induces expression of FMRFamidelike neuropeptides, which modulate pain. The neuropeptides slowed inactivation and induced sustained currents during acidification. The effects were specific; different channels showed distinct responses to the various peptides. These results suggest that acid-sensing ion channels may integrate multiple extracellular signals to modify sensory perception.
Dec Progr Brain Res. This chapter focuses on the tissue acidosis in nociception and pain. Local imbalance of perfusion and metabolism may be suggested to be the common mechanism generating tissue acidosis.
Even in inflammation, the metabolic turn-over may be more enhanced, for example, by accumulation of inflammatory cells, than the local blood flow that should lead to lactic acid accumulation. Leukocytes, as well as myocytes, can actively transport lactic acid into the interstitial space. The delayed hyperalgesia observed with experimental tissue acidosis in humans seems to be reflected in a concomitantly delayed decrease of mechanical thresholds of cutaneous nociceptors, in vitro, which occurs upon repeated or prolonged exposure to low pH.
A striking feature of pH-induced pain and nociceptor excitation is the synergism with mediators of inflammation encountered with tissue acidosis in inflamed areas. Preventing tissue acidosis may neither be possible nor even desirable; however, blocking pH-induced nociceptor excitation may be of great help to controlling pain of various origins. Beyond homologies with the spinal dorsal horn. Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Cardiac afferents are sensory neurons that mediate angina, pain that occurs when the heart receives insufficient blood supply for its metabolic demand ischemia.
These neurons display enormous acid-evoked depolarizing currents, and they fire action potentials in response to extracellular acidification that accompanies myocardial ischemia. Here we show that acid-sensing ion channel 3 ASIC3 , but no other known acid-sensing ion channel, reproduces the functional features of the channel that underlies the large acid-evoked current in cardiac afferents.
Particularly important is the ability of ASIC3 and the native channel to open at pH 7, a value reached in the first few minutes of a heart attack. The steep activation curve suggests that the channel opens when four protons bind. Analgesic profile of peroral and topical ketoprofen upon low pH-induced muscle pain. Topical analgesics are widely marketed for treatment of muscle and joint pain. We have recently developed a model of muscle pain and have used this model to evaluate the efficacy of commercially available topical and peroral ketoprofen in order to evaluate the time- and dose-dependence of analgesia.
In the present study, we examined the dose- 0, 50, and mg and time-dependence hourly to 8 h of commercially available peroral and topical ketoprofen.
In order to achieve infusion times of 8 h and thus study the time course of analgesic action , we adapted the model of low pH-induced muscle pain in humans to these requirements by applying the infusions continuously for 10 min every hour for 8 h. We found that the 10 min infusion produced reliable and consistent pain levels that were reproducible over the 8 h of the study.
The study was performed double-blind, randomized, and with a 1-week interval between each of five different sessions cross-over. Altogether six volunteers underwent intramuscular infusions of isotonic phosphate-buffered saline solution of pH 5. Twenty minutes after starting the infusion the volunteers received a capsule with either a placebo or 50 or mg ketoprofen perorally and, in addition, either placebo gel or 50 or mg of a 2. One of the sessions included a placebo gel and an oral placebo.
In contrast, pain reduction after topical ketoprofen application was not of the same magnitude but appeared to be faster to develop with a maximum effect within 1 h on average. The maximum pain suppression with mg topical 2. The apparent analgesia was rapid to develop but transient and pain ratings increased back to baseline values within 3 h for the mg dose and within 2 h for the 50 mg dose.
This data suggests that topical application of commercial gel-based systems does not provide long-lasting analgesia in the muscle when compared to perorally-dosed ketoprofen. In addition, the data show that even doses of mg peroral ketoprofen do not provide complete relief of muscle pain.
The injection of the small-fibre excitant and inflammatory irritant mustard oil MO into the temporomandibular joint TMJ region of rats evokes a sustained and reversible increase in electromyographic EMG activity of jaw muscles. The 'rekindling' of this nociceptive reflex by intrathecal i.
Loss of DRASIC increased the sensitivity of mechanoreceptors detecting light touch, but it reduced the sensitivity of a mechanoreceptor responding to noxious pinch and decreased the response of acid- and noxious heat-sensitive nociceptors. Moreover, in different cellular contexts, DRASIC may respond to mechanical stimuli or to low pH to mediate normal touch and pain sensation.
Effects of NMDA and non-NMDA ionotropic glutamate receptor antagonists on the development and maintenance of hyperalgesia induced by repeated intramuscular injection of acidic saline. Two unilateral injections of pH 4. This decrease is significant by 4h and lasts through 1 week. The purpose of this study was to characterize the involvement of both N-methyl-D-aspartate NMDA and non-NMDA glutamate receptors in the spinal cord dorsal horn in the development and maintenance of mechanical hyperalgesia from repeated intramuscular injections of acidic saline.
Drugs were administered at one of three different time points: Mechanical withdrawal thresholds were measured with von Frey filaments before, 4h, and 24h after injection 1 and before, 4h, 24h, and 1 week after injection 2.
AP5 had no effect on mechanical withdrawal thresholds when administered prior to the first intramuscular injection of pH 4. When AP5 was administered before the second intramuscular injection, the bilateral decrease in mechanical withdrawal thresholds was delayed for up to 24h. Intrathecal administration of AP5 1 week after the second intramuscular injection of pH 4. Blockade of non-NMDA glutamate receptors in the spinal cord dorsal horn prior to either the first or second intramuscular injection of pH 4.
The co-expression of ASIC3 with calcitonin gene-related peptide and parvalbumin in the rat trigeminal ganglion. ASIC3-IR neurons which have large myelinated axons may be common in the tooth pulp but not the facial skin. Chronic muscle pain induced by repeated acid Injection is reversed by spinally administered mu- and delta-, but not kappa-, opioid receptor agonists. Opioids are commonly used for pain relief clinically and reduce hyperalgesia in most animal models. Two injections of acidic saline into one gastrocnemius muscle 5 days apart produce a long-lasting bilateral hyperalgesia without associated tissue damage.
The current study was undertaken to assess the effects of opioid agonists on mechanical hyperalgesia induced by repeated intramuscular injections of acid.
Morphine mu-agonist , [D-Ala 2 ,N-Me-Phe 4 ,Gly-ol 5 ]-enkephalin mu-agonist; DAMGO , 4-[ alpha R -alpha- 2S,5R allyl-2,5-dimethylpiperazinyl methoxybenzyl]-N,N-diethylbenzamide delta-agonist; SNC80 , or 1S-trans -3,4-dichloro-N-methyl-N-[2- 1-pyrrolidinyl cylcohexyl]-benzeneacetamide hydrochloride kappa-agonist; U50, were administered intrathecally to activate opioid receptors once hyperalgesia was developed.
Mechanical hyperalgesia was assessed by measuring the withdrawal thresholds to mechanical stimuli von Frey filaments before the first and second intramuscular injection, 24 h after the second intramuscular injection, and for 1 h after administration of the opioid agonist or vehicle. U50, had no effect on the decreased mechanical withdrawal thresholds. Thus, activation of mu- and delta-, but not kappa-, opioid receptors in the spinal cord reduces mechanical hyperalgesia following repeated intramuscular injection of acid, thus validating the use of this new model of chronic muscle pain.
Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. Many painful inflammatory and ischemic conditions such as rheumatoid arthritis, cardiac ischemia, and exhausted skeletal muscles are accompanied by local tissue acidosis.
In such acidotic states, extracellular protons provoke the pain by opening cation channels in nociceptors. It is generally believed that a vanilloid receptor subtype-1 VR1 and an acid-sensing ion channel ASIC mediate the greater part of acid-induced nociception in mammals. Here we provide evidence for the involvement of both channels in acid-evoked pain in humans and show their relative contributions to the nociception.
Under more severe acidification pH 5. In addition, capsazepine had a partial blocking effect under these conditions. Amiloride itself neither blocked capsaicin-evoked localized pain in human skin nor inhibited proton-induced currents in VR1-expressing Xenopus oocytes. Our results suggest that ASICs are leading acid sensors in human nociceptors and that VR1 participates in the nociception mainly under extremely acidic conditions.
Acid-sensing ion channels ASICs open when extracellular pH drops and they are enhanced by lactate, making them specialized for detecting lactic acidosis. Highly expressed on cardiac nociceptors and some other sensory neurons, ASICs may help trigger pain caused by tissue ischemia.
Chemical phenotypes of muscle and cutaneous afferent neurons in the rat trigeminal ganglion. Retrograde labeling was combined with cytochemistry to investigate phenotypic differences in primary afferent neurons relaying sensory information from deep and superficial craniofacial tissues. Somata labeled from muscle were larger than cutaneous afferent neurons.
Muscle afferent neurons exhibited positive staining as follows: The somata of CGRP- and SP-positive muscle afferent neurons were smaller than that of the overall muscle afferent population. Size differences were not detected between IB4- or ChTB-binding muscle afferent neurons and the total muscle afferent population. The following distribution was found for cutaneous afferent neurons: Cutaneous afferent neurons positive for SP were smaller, while ChTB-binding cutaneous afferents were larger than the overall cutaneous afferent population.
The number of retrogradely labeled neurons never differed between sexes. The percentage of retrogradely labeled muscle afferent neurons that were CGRP-positive was greater in males than females. These data indicate the presence of phenotypic, target, and sex differences in trigeminal ganglion primary afferent neurons.
Aug J Neurosci. Spinal activation of the cAMP pathway produces mechanical hyperalgesia, sensitizes nociceptive spinal neurons, and phosphorylates the transcription factor cAMP-responsive element binding protein CREB , which initiates gene transcription. This study examined the role of the cAMP pathway in a model of chronic muscle pain by assessing associated behavioral changes and phosphorylation of CREB.
Bilateral mechanical hyperalgesia of the paw was induced by administering two injections of acidic saline, 5 d apart, into the gastrocnemius muscle of male Sprague Dawley rats. Spinal blockade of adenylate cyclase prevents the expected increase in p-CREB that occurs after intramuscular acid injection. The reversal of mechanical hyperalgesia by adenylate cyclase or protein kinase A inhibitors spinally follows a similar pattern with reversal at 24 hr, but not 1 week, compared with the vehicle controls.
The p-CREB immunoreactivity in the superficial dorsal horn correlates with the mechanical withdrawal threshold such that increases in p-CREB are associated with decreases in threshold. Therefore, activation of the cAMP pathway in the spinal cord phosphorylates CREB and produces mechanical hyperalgesia associated with intramuscular acid injections. The mechanical hyperalgesia and phosphorylation of CREB depend on early activation of the cAMP pathway during the first 24 hr but are independent of the cAMP pathway by 1 week after intramuscular injection of acid.
Clinically, chronic pain and hyperalgesia induced by muscle injury are disabling and difficult to treat. Cellular and molecular mechanisms underlying chronic muscle-induced hyperalgesia are not well understood.
For this reason, we developed an animal model where repeated injections of acidic saline into one gastrocnemius muscle produce bilateral, long-lasting mechanical hypersensitivity of the paw i. Since acid sensing ion channels ASICs are found on primary afferent fibers and respond to decreases in pH, we tested the hypothesis that ASICs on primary afferent fibers innervating muscle are critical to development of hyperalgesia and central sensitization in response to repeated intramuscular acid.
Mechanical hyperalgesia produced by repeated intramuscular acid injections is prevented by prior treatment of the muscle with the non-selective ASIC antagonist, amiloride, suggesting ASICs might be involved. ASIC3 knockouts do not develop mechanical hyperalgesia to repeated intramuscular acid injection when compared to wildtype littermates. In contrast, ASIC1 knockouts develop hyperalgesia similar to their wildtype littermates.
Extracellular recordings of spinal wide dynamic range WDR neurons from wildtype mice show an expansion of the receptive field to include the contralateral paw, an increased response to von Frey filaments applied to the paw both ipsilaterally and contralaterally, and increased response to noxious pinch contralaterally after the second intramuscular acid injection.
Thus, activation of ASIC3s on muscle afferents is required for development of mechanical hyperalgesia and central sensitization that normally occurs in response to repeated intramuscular acid. Therefore, interfering with ASIC3 might be of benefit in treatment or prevention of chronic hyperalgesia. Pharmacological characterisation of acid-induced muscle allodynia in rats. Previous studies have shown that repeated injections of acidic saline, given into the lateral gastrocnemius muscle of rats, results in a bilateral reduction in withdrawal threshold to tactile stimulation of the hindpaws.
We have now characterised this model of muscoskeletal pain pharmacologically, by evaluating the antinociceptive effects of various analgesics after systemic administration. All antinociceptive effects were observed at nonataxic doses as determined by the rotarod test. These results suggest that in this model, muscle-mediated pain can be alleviated by various analgesics with differing mechanisms of action, and that once established ongoing inflammation does not appear to contribute to this process.
Linking work factors to neck myalgia: The pathophysiological link between work-related exposures and neck myalgia remains a puzzle. According to the hypothesis presented here, neck myalgia is evoked when low-level contractions in the trapezius muscle are combined with sympathetic vasoconstriction due to psychological stress or prolonged head-down neck flexion at work.
High estrogen-level, which gives a high expression of nitric oxide synthase in the muscle, accentuates the situation. During episodes of sustained inhibition of cytochrome oxidase by nitric oxide, peroxynitrite may be produced and cause irreversible inactivation of several enzymes in the mitochondrial electron-carrier chain.
With repeated episodes, an increasing part of the enzymatic capacity for cellular respiration is inactivated. Even if this process only takes place within a small portion of the muscle fibres, it may contribute to frequent exacerbations of pain.
Effects of peroxinitrite may also explain the mitochondrial abnormalities found in the trapezius muscle of many neck myalgia patients. Adrenergic antagonists and nitric oxide synthase inhibitors could reduce symptoms.
Ascorbic acid, alpha tocopherol, and flavonoids, which are safe and effective scavengers of peroxynitrite, could prevent chronicity.
The most effective non-pharmacological measure may be to reduce exposure to prolonged head-down neck flexions and psychosocial stress at work. Acidic pH and capsaicin activate mechanosensitive group IV muscle receptors in the rat. Strenuous exercise of muscle as well as inflammation and ischaemia are associated with tissue acidosis. However, so far, nothing is known about the sensitivity to hydrogen ions of slowly conducting muscle afferent units.
The study investigated if acid-sensing ion channels, e.
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Von Frey hair tactile sensitivity .. 40 . Von Frey hair mechanosensitivity. Drugs and reagents. Colonic Mucosal Viability Other Specific Novel Mechanosensitivity and Classification of Colonic Afferent fibres 3. Abstract . Response of a mucosal afferent to calibrated Von Frey hairs and two chemical stimuli. Table Conduction velocity, von Frey hair thresholds, heat Mechanical stimulation. The mechanical threshold of each unit was determined with heat-cold sensitive nociceptor; CLTM, C low threshold mechanosensitive fibre;.